This project area builds on previous observations (Blood 85: 3457, 1995 and Blood 88:1188, 1996) that immunotoxins constructed with deglycosylated ricin A chain and murine monoclonal antibodies directed to anti-CD22 and anti-CD19 determinants respectively could be given safely to patients and in the case of the anti-CD22 reagent cause meaningful responses. We had previously completed a Phase I study of the combination of the anti-CD19 + anti-CD22 immunotoxins, based on pre clinical data that the combination might be more effective. Unfortunately, we encountered dose-limiting toxicity in a way that did not correlate with dose. This consisted of vascular leak syndrome and a hemolytic-uremic syndrome in previously irradiated patients. Laboratory studies support the concept that aggreggation of the CD19 immunotoxin also may have contributed to this phenomenon. Preclinical studies have defined a safe storage and thawing procedure that minimizes aggregation of immunotoxin. These studies have recently been published(Clin. Cancer Res. 6:1302-1313, 2000). The future plan is to focus on a highly purified "monovalent" immunotoxin where one A chain is joined to one antibody molecule as a single agent. The protocol to accomplish this has been approved by the NCI IRB and will commence in late 2000.